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KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD

Journal article
Authors C. M. Erickson
S. A. Schultz
J. M. Oh
B. F. Darst
Y. Ma
D. Norton
T. Betthauser
C. L. Gallagher
C. M. Carlsson
B. B. Bendlin
S. Asthana
B. P. Hermann
M. A. Sager
Kaj Blennow
Henrik Zetterberg
C. D. Engelman
B. T. Christian
S. C. Johnson
D. B. Dubal
O. C. Okonkwo
Published in Neurology
Volume 92
Issue 16
Pages E1878-E1889
ISSN 0028-3878
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages E1878-E1889
Language en
Links dx.doi.org/10.1212/wnl.000000000000...
Keywords apolipoprotein-e, alzheimers-disease, functional variant, cognitive, decline, epsilon-4 allele, beta, association, gene, risk, apoe, Neurosciences & Neurology
Subject categories Clinical Medicine

Abstract

Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated beta-amyloid (A beta) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on A beta burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on A beta was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater A beta burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on A beta load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0.001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher A beta burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated A beta aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

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